Antinociceptive activity of new imidazolidine carbonyl derivatives. Part 4. Synthesis and pharmacological activity of 8-aryl-3,4-dioxo-2H,8H-6,7-dihydroimidazo[2,1-c] [1,2,4]triazines.

Abstract

Synthesis and pharmacological activity of 8-aryl-3,4-dioxo-2H,8H-6,7-dihydroimidazo[2,1-c] [1,2,4]triazines (A) are presented. The title compounds were obtained from 1-aryl-2-hydrazinoimidazolines (1) by cyclization reaction with ethyl oxalate (2). They were tested for pharmacological activity in behavioral animal tests (A1, A3, A5, A6, A8, A9). With relatively low acute toxicity (LD50 in range from 1100 to over 2000 mg kg(-1), intraperitoneally, i.p.), some of them exhibited significant antinociceptive activity as the result of the 'writhing' test indicated. Especially strong antinociception for compound A8 and significant for A6 was observed in doses of 12.5-200 mg (0.00625-0.1 LD50) and 37.5-150 mg (0.025-0.1 LD50), respectively. Reversion of the antinociception for A1 and A8 produced in the 'writhing' test by 5 mg kg(-1) dose of naloxon can suggest an opioid-like mechanism of their analgesic activity. Additionally, compound A9 reduced number of the "head twitch" episodes after 5-hydroxytryptophan (5-HTP) administration with no antinociceptive effect at all and compound A3 showed significant protection in the pentylentetrazol-induced seizure model. Differences observed in the activity spectrum between A8 and A9 derivatives can be explained on the base of difference in the amido-imido tautomeric equilibrium observed between these two compounds.

• Authors: Krzysztof Sztanke, Sylwia Fidecka, Ewa Kedzierska, Zbigniew Karczmarzyk, Kalevi Pihlaja, Dariusz Matosiuk
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 40 Issue 2 Pg. 127-34 (Feb 2005) ISSN: 0223-5234 [Print] France
• PMID: 15694647 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Amides
• Analgesics
• Analgesics, Opioid
• Imidazoles
• Imidazolidines
• Imides
• Triazines
• Serotonin
• Carbonic Acid
• Pentylenetetrazole

Topics

• Amides (chemistry)
• Analgesics (chemical synthesis, pharmacology)
• Analgesics, Opioid (chemistry, metabolism)
• Animals
• Behavior, Animal (drug effects)
• Carbonic Acid (chemistry)
• Cyclization
• Imidazoles (chemical synthesis, pharmacology)
• Imidazolidines (chemical synthesis, metabolism, pharmacology)
• Imides (chemistry)
• Models, Chemical
• Pentylenetetrazole (pharmacology)
• Seizures (chemically induced)
• Serotonin (chemistry, metabolism)
• Triazines (chemical synthesis, pharmacology)